A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p

The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. We have studied two large inbred families of different ethnic origin and excluded linkage to LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceeding to a genomic linkage search, we have now identified linkage to markers D2S134 and D2S136 on chromosome 2p (maximum lod score 3.57 at zero recombination). The phenotype in the two families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression. This work identifies a second locus for autosomal recessive limb-girdle muscular dystrophy.     

A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1

Lumbosacral defects on 20 patients were covered with a perforator-based flap. Cutaneous perforators derived from the 9th and 10th intercostal arteries, the 4th lumbar artery, and multiple gluteal perforators that penetrate the gluteus maximus muscle were used as vascular pedicles. Minor complications occurred in five cases. Using this method, minimal morbidity of the donor site is expected because the gluteus maximus need not be sacrificed. Accordingly, perforator-based flaps are especially indicated for ambulatory patients, but for paraplegic patients as well. Even in the event of recurrence, another perforator-based or musculocutaneous flap can be elevated from the ipsilateral side because of the presence of multiple perforators in the lumbosacral and gluteal regions.     

A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q

In contrast to the frequent dominant optic atrophies (DOAs) in which the neuropathy is usually an isolated event, isolated recessive optic atrophies (ROAs) are very uncommon and have been described as severe congenital or early infantile conditions. To date, two loci for isolated DOA have been mapped, of which one was ascribed to mutations in the OPA1 gene. Conversely, no isolated autosomal ROA locus had previously been localised. Here, we report a large multiplex consanguineous family of French origin affected with an early onset but slowly progressive form of isolated OA. A genome-wide search for homozygosity allowed the localisation of the disease-causing gene to chromosome 8q21-q22 (Zmax of 3.41 at theta=0 for D8S270), in a 12 Mb interval flanked by markers D8S1702 and D8S1794. This localisation excludes allelism of the disease with both isolated DOAs, on one hand, or all known syndromic forms of ROA, on the other hand, supporting the mapping of a first gene for isolated autosomal ROA (ROA1) on the long arm of chromosome 8.     

A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13

Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder characterized by fine, slow-growing scalp and body hair, sparse eyebrows and eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03.     

Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

Distal myopathy with rimmed vacuoles is an autosomal recessive muscular disorder, characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood. Recently, the gene locus for familial vacuolar myopathy with autosomal recessive inheritance (hereditary inclusion body myopathy) was mapped to chromosome 9 by genome-wide linkage analysis of nine Persian-Jewish families. Since both disease conditions share similar clinical, genetic, and histopathological features, we analyzed seven families with distal myopathy with rimmed vacuoles using ten microsatellite markers within the region of the hereditary inclusion body myopathy locus. Significantly high cumulative pairwise lod scores were obtained with three markers: D9S248 (Z(max) = 5.90 at theta = 0), D9S43 (Z(max) = 5.25 at theta = 0), and D9S50 (Z(max) = 4.23 at theta = 0). Detection of obligate recombination events as well as multipoint linkage analysis revealed that the most likely location of the distal myopathy with rimmed vacuoles gene is in a 23.3-cM interval defined by D9S319 and D9S276 on chromosome 9. The results raise the possibility that distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy in Persian Jews are allelic diseases.     

A gene for familial juvenile polyposis maps to chromosome 18q21.1

Bacillus subtilis cells respond almost immediately to different stress conditions by increasing the production of general stress proteins (GSPs). The genes encoding the majority of the GSPs that are induced by heat, ethanol, salt stress or by starvation for glucose, oxygen or phosphate belong to the sigmaB-dependent general stress regulon. Despite a good understanding of the complex regulation of the activity of sigmaB and knowledge of a very large number of general stress genes controlled by sigmaB, first insights into the physiological role of this nonspecific stress response have been obtained only very recently. To explore the physiological role of this reguIon, we and others identified sigmaB-dependent general stress genes and compared the stress tolerance of wild-type cells with mutants lacking sigmaB or general stress proteins. The proteins encoded by sigmaB-dependent general stress genes can be divided into at least five functional groups that most probably provide growth-restricted B. subtilis cells with a multiple stress resistance in anticipation of future stress. In particular, sigB mutants are impaired in non-specific resistance to oxidative stress, which requires the sigmaB-dependent dps gene encoding a DNA-protecting protein. Protection against oxidative damage of membranes, proteins or DNA could be the most essential component of sigmaB mediated general stress resistance in growth-arrested aerobic gram-positive bacteria. Other general stress genes have both a sigmaB-dependent induction pathway and a second sigmaB-independent mechanism of stress induction, thereby partially compensating for a sigmaB deficiency in a sigB mutant. In contrast to sigB mutants, null mutations in genes encoding those proteins, such as cIpP or cIpC, cause extreme sensitivity to salt or heat.     

A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24-q25

A novel human cDNA with a predicted protein homologous to the carboxyl end of lysyl oxidase, an extracellular enzyme involved in the maturation of collagen and elastin, has been isolated. The homology to lysyl oxidase begins exactly at the position of the exon 1/exon 2 boundary in the mouse gene (Contente, S., Csiszar, K., Kenyon, K., and Friedman, R. M. (1993) Genomics 16, 395-400). This lysyl oxidase-like gene, which appears to be no larger than 22.1 kilobases, codes for a single polyadenylated RNA species of 2.48 kilobases and has been mapped to chromosome 15q24-q25.     

Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.     

A gene (ETM) for essential tremor maps to chromosome 2p22-p25

We report the results of linkage analysis in a large American family of Czech descent with dominantly inherited "pure" essential tremor (ET) and genetic anticipation. Genetic loci on chromosome 2p22-p25 establish linkage to this region with a maximum LOD score (Zmax) = 5.92 for the locus, D2S272. Obligate recombinant events place the ETM gene in a 15-cM candidate interval between the genetic loci D2S168 and D2S224. Repeat expansion detection analysis suggests that expanded CAG trinucleotide sequences are associated with ET. These findings will facilitate the search for an ETM gene and may further our understanding of the human motor system.     

A potential human axonemal dynein heavy-chain gene maps to 17q25

Destruction of the membranous labyrinth can lead to sensorineural hearing loss. This is especially frequent in surgery for active otorrhea. However, destruction of the posterior labyrinth sometimes can be solved without loss of cochlear function. We report three cases of partial labyrinthectomy for intralabyrinthine cholesteatoma without functional loss. Current theories regarding the conservation of hearing are discussed.     

P450RAI (CYP26A1) maps to human chromosome 10q23-q24 and mouse chromosome 19C2-3

STUDY DESIGN: A case report. OBJECTIVES: To document a fracture of the 11th thoracic vertebra after spine fusion for adult idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Three cases of vertebral fractures associated with spine fusion for scoliosis were found in the literature. METHODS: Medical and radiologic records and related literature were reviewed. RESULTS: A 30-year-old woman had undergone anterior and posterior fusion with Cotrel-Dubousset instrumentation for progressive idiopathic scoliosis. Two years after surgery, she was in a car accident. A radiographic study and computer tomographic scanning depicted a fracture of T11 and bending of the rods. Observation was instituted and symptoms resolved. CONCLUSIONS: Fracture of a vertebra within an extensive spine fusion for scoliosis is rare. The 360 degrees solid fusion together with strong posterior instrumentation may have had some protective effect in this patient.     

The gene for glycogen-storage disease type 1b maps to chromosome 11q23

Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.     

A second locus for familial high myopia maps to chromosome 12q

Myopia, or nearsightedness, is the most common eye disorder worldwide. "Pathologic" high myopia, or myopia of <=-6.00 diopters, predisposes individuals to retinal detachment, macular degeneration, cataract, or glaucoma. A locus for autosomal dominant pathologic high myopia has been mapped to 18p11.31. We now report significant linkage of high myopia to a second locus at the 12q21-23 region in a large German/Italian family. The family had no clinical evidence of connective-tissue abnormalities or glaucoma. The average age at diagnosis of myopia was 5.9 years. The average spherical-component refractive error for the affected individuals was -9.47 diopters. Markers flanking or intragenic to the genes for the 18p locus, Stickler syndromes type I and II (12q13.1-q13.3 and 6p21.3), Marfan syndrome (15q21.1), and juvenile glaucoma (chromosome 1q21-q31) showed no linkage to the myopia in this family. The maximum LOD score with two-point linkage analysis in this pedigree was 3.85 at a recombination fraction of .0010, for markers D12S1706 and D12S327. Recombination events identified markers D12S1684 and D12S1605 as flanking markers that define a 30.1-cM interval on chromosome 12q21-23, for the second myopia gene. These results confirm genetic heterogeneity of myopia. The identification of this gene may provide insight into the pathophysiology of myopia and eye development.     

A new locus for hemiplegic migraine maps to chromosome 1q31

A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.     

The gene for bovine interferon gamma (IFNG) maps to the q22-q24 bands of chromosome 5 in cattle

In 19 children who received renal transplants, 6 developed genu valgum one to two years after the transplantation. Except for one patient, biochemical blood and urine parameters were normal and bone radiograph showed no signs of renal osteodystrophy during this period. Two patients had bilateral varus supracondylar osteotomy, and in one patient medial hemistapling of the distal femur was performed.     

The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q

Progressive myoclonus epilepsy of the Lafora type (Lafora's disease) is an autosomal recessive disease characterized by epilepsy, myoclonus, dementia, and periodic acid-Schiff-positive intracellular inclusion bodies. The inclusion deposits consist of branched polysaccharides (polyglucosans) but the responsible biochemical defect has not been identified. Onset is during late childhood or adolescence and the disease leads to a fatal outcome within a decade of first symptoms. We studied nine families in which Lafora's disease had been proven by biopsy in at least one member. In order to locate the responsible gene, we screened the human genome with microsatellite markers spaced an average of 13 cM. We used linkage analysis in all nine families and homozygosity mapping in four consanguineous families to define the Lafora's disease gene region. Two point linkage analysis resulted in a total peak lod score of 10.54 for marker D6S311. Six additional chromosome 6q23-25 microsatellites yielded lod scores ranging from 5.92 to 9.60 at theta m = f = 0. An extended pedigree with five affected members independently proved linkage with peak lod scores over 3.8 at theta m = f = 0 for D6S292, D6S403, and D6S311. The multipoint one-lod-unit support interval covered a 2.5 cM region surrounding D6S403. Homozygosity mapping defined a 17 cM region in chromosome 6q23-25 flanked by D6S292 and D6S420 that contains the Lafora's disease gene.     

The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36

We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The clinical association of sensorineural hearing loss with pili torti (broken, twisted hairs) was described >30 years ago by Bjornstad; subsequently, several small families have been studied. We evaluated a large kindred with Bjornstad syndrome in which eight members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between loci D2S1371 and D2S163. We speculate that intermediate filament and intermediate filament-associated proteins are good candidate genes for causing Bjornstad syndrome.     

A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3

Familial hypertrophic cardiomyopathy (FHC) is caused by missense mutations in the beta cardiac myosin heavy chain (MHC) gene in less than half of affected individuals. To identify the location of another gene involved in this disorder, a large family with FHC not linked to the beta MHC gene was studied. Linkage was detected between the disease in this family and a locus on chromosome 1q3 (maximum multipoint lod score = 8.47). Analyses in other families with FHC not linked to the beta MHC gene, revealed linkage to the chromosome 1 locus in two and excluded linkage in six. Thus mutations in at least three genetic loci can cause FHC. Three sarcomeric contractile proteins--troponin I, tropomyosin and actin--are strong candidate FHC genes at the chromosome 1 locus.